Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid
The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufactur...
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description | The introduction of type b
Haemophilus influenzae
conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction. |
doi_str_mv | 10.1007/s10719-011-9344-3 |
format | Article |
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Haemophilus influenzae
conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.</description><identifier>ISSN: 0282-0080</identifier><identifier>EISSN: 1573-4986</identifier><identifier>DOI: 10.1007/s10719-011-9344-3</identifier><identifier>PMID: 21850577</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Algorithms ; Amines - chemistry ; Amines - immunology ; Bacterial Capsules - immunology ; Biochemistry ; Biomedical and Life Sciences ; Capsular polysaccharides ; Design optimization ; Developing Countries ; Diffusion ; Drug therapy ; glycoconjugates ; Haemophilus Infections - immunology ; Haemophilus Infections - prevention & control ; Haemophilus influenzae ; Haemophilus influenzae type b - immunology ; Haemophilus influenzae type b - pathogenicity ; Haemophilus Vaccines - chemical synthesis ; Haemophilus Vaccines - immunology ; Humans ; Hydrazines - chemistry ; Hydrazines - immunology ; Immunoconjugates - chemistry ; Immunogenicity ; Influenza ; Isoelectric points ; Life Sciences ; Lysine ; Lysine - chemistry ; Lysine - immunology ; Pathology ; Polysaccharides - chemistry ; Polysaccharides - immunology ; Polysaccharides, Bacterial - chemistry ; Polysaccharides, Bacterial - immunology ; Precipitation ; Research Design ; Salts ; Temperature effects ; Tetanus ; Tetanus Toxoid - chemistry ; Tetanus Toxoid - immunology ; Vaccination ; Vaccines ; Vaccines, Conjugate - chemistry ; Vaccines, Conjugate - immunology</subject><ispartof>Glycoconjugate journal, 2011-10, Vol.28 (7), p.463-472</ispartof><rights>Springer Science+Business Media, LLC 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-e9a439006f95f216d64d14cc7528e203e1d88b02e8ed2ae2d9eb51ce93c3d5903</citedby><cites>FETCH-LOGICAL-c402t-e9a439006f95f216d64d14cc7528e203e1d88b02e8ed2ae2d9eb51ce93c3d5903</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10719-011-9344-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10719-011-9344-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27931,27932,41495,42564,51326</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21850577$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Laferriere, Craig</creatorcontrib><creatorcontrib>Ravenscroft, Neil</creatorcontrib><creatorcontrib>Wilson, Seanette</creatorcontrib><creatorcontrib>Combrink, Jill</creatorcontrib><creatorcontrib>Gordon, Lizelle</creatorcontrib><creatorcontrib>Petre, Jean</creatorcontrib><title>Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid</title><title>Glycoconjugate journal</title><addtitle>Glycoconj J</addtitle><addtitle>Glycoconj J</addtitle><description>The introduction of type b
Haemophilus influenzae
conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.</description><subject>Algorithms</subject><subject>Amines - chemistry</subject><subject>Amines - immunology</subject><subject>Bacterial Capsules - immunology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Capsular polysaccharides</subject><subject>Design optimization</subject><subject>Developing Countries</subject><subject>Diffusion</subject><subject>Drug therapy</subject><subject>glycoconjugates</subject><subject>Haemophilus Infections - immunology</subject><subject>Haemophilus Infections - prevention & control</subject><subject>Haemophilus influenzae</subject><subject>Haemophilus influenzae type b - immunology</subject><subject>Haemophilus influenzae type b - pathogenicity</subject><subject>Haemophilus Vaccines - chemical synthesis</subject><subject>Haemophilus Vaccines - immunology</subject><subject>Humans</subject><subject>Hydrazines - chemistry</subject><subject>Hydrazines - immunology</subject><subject>Immunoconjugates - chemistry</subject><subject>Immunogenicity</subject><subject>Influenza</subject><subject>Isoelectric points</subject><subject>Life Sciences</subject><subject>Lysine</subject><subject>Lysine - chemistry</subject><subject>Lysine - immunology</subject><subject>Pathology</subject><subject>Polysaccharides - chemistry</subject><subject>Polysaccharides - immunology</subject><subject>Polysaccharides, Bacterial - chemistry</subject><subject>Polysaccharides, Bacterial - immunology</subject><subject>Precipitation</subject><subject>Research Design</subject><subject>Salts</subject><subject>Temperature effects</subject><subject>Tetanus</subject><subject>Tetanus Toxoid - chemistry</subject><subject>Tetanus Toxoid - immunology</subject><subject>Vaccination</subject><subject>Vaccines</subject><subject>Vaccines, Conjugate - chemistry</subject><subject>Vaccines, Conjugate - immunology</subject><issn>0282-0080</issn><issn>1573-4986</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kT1vFDEQhi0EIkfCD6BBFg2VYez9sksUJQQpUpqktnz27J1Pu_ay9obcdfxzfLoAEhKVi3ned6x5CHnH4RMH6D4nDh1XDDhnqqprVr0gK950FauVbF-SFQgpGICEM_ImpR2UTC3ka3ImuGyg6boV-Xn1NOHsRwzZDNRh8ptAc6Rxyn70B6Qm0BuDY5y2flgS9aEfFgwHgzTvJ6RramPYLRuTkT4aa31AOhqH9IfPW7rdu9kcvEPmypJHk0ujoxmzCaUrx6fo3QV51Zsh4dvn95w8XF_dX96w27uv3y6_3DJbg8gMlakrBdD2qukFb11bO15b2zVCooAKuZNyDQIlOmFQOIXrhltUla1co6A6Jx9PvdMcvy-Ysh59sjgMJmBcklbllh2Xsinkh3_IXVzmUD6npap5qzo4QvwE2TmmNGOvp3JGM-81B320o092dLGjj3Z0VTLvn4uX9YjuT-K3jgKIE5DKKGxw_rv5_62_AJFEnMQ</recordid><startdate>20111001</startdate><enddate>20111001</enddate><creator>Laferriere, Craig</creator><creator>Ravenscroft, Neil</creator><creator>Wilson, Seanette</creator><creator>Combrink, Jill</creator><creator>Gordon, Lizelle</creator><creator>Petre, Jean</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7QL</scope><scope>7U9</scope><scope>C1K</scope></search><sort><creationdate>20111001</creationdate><title>Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid</title><author>Laferriere, Craig ; Ravenscroft, Neil ; Wilson, Seanette ; Combrink, Jill ; Gordon, Lizelle ; Petre, Jean</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-e9a439006f95f216d64d14cc7528e203e1d88b02e8ed2ae2d9eb51ce93c3d5903</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Algorithms</topic><topic>Amines - chemistry</topic><topic>Amines - immunology</topic><topic>Bacterial Capsules - immunology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Capsular polysaccharides</topic><topic>Design optimization</topic><topic>Developing Countries</topic><topic>Diffusion</topic><topic>Drug therapy</topic><topic>glycoconjugates</topic><topic>Haemophilus Infections - immunology</topic><topic>Haemophilus Infections - prevention & control</topic><topic>Haemophilus influenzae</topic><topic>Haemophilus influenzae type b - immunology</topic><topic>Haemophilus influenzae type b - pathogenicity</topic><topic>Haemophilus Vaccines - chemical synthesis</topic><topic>Haemophilus Vaccines - immunology</topic><topic>Humans</topic><topic>Hydrazines - chemistry</topic><topic>Hydrazines - immunology</topic><topic>Immunoconjugates - chemistry</topic><topic>Immunogenicity</topic><topic>Influenza</topic><topic>Isoelectric points</topic><topic>Life Sciences</topic><topic>Lysine</topic><topic>Lysine - chemistry</topic><topic>Lysine - immunology</topic><topic>Pathology</topic><topic>Polysaccharides - chemistry</topic><topic>Polysaccharides - immunology</topic><topic>Polysaccharides, Bacterial - chemistry</topic><topic>Polysaccharides, Bacterial - immunology</topic><topic>Precipitation</topic><topic>Research Design</topic><topic>Salts</topic><topic>Temperature effects</topic><topic>Tetanus</topic><topic>Tetanus Toxoid - chemistry</topic><topic>Tetanus Toxoid - immunology</topic><topic>Vaccination</topic><topic>Vaccines</topic><topic>Vaccines, Conjugate - chemistry</topic><topic>Vaccines, Conjugate - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Laferriere, Craig</creatorcontrib><creatorcontrib>Ravenscroft, Neil</creatorcontrib><creatorcontrib>Wilson, Seanette</creatorcontrib><creatorcontrib>Combrink, Jill</creatorcontrib><creatorcontrib>Gordon, Lizelle</creatorcontrib><creatorcontrib>Petre, Jean</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Glycoconjugate journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Laferriere, Craig</au><au>Ravenscroft, Neil</au><au>Wilson, Seanette</au><au>Combrink, Jill</au><au>Gordon, Lizelle</au><au>Petre, Jean</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid</atitle><jtitle>Glycoconjugate journal</jtitle><stitle>Glycoconj J</stitle><addtitle>Glycoconj J</addtitle><date>2011-10-01</date><risdate>2011</risdate><volume>28</volume><issue>7</issue><spage>463</spage><epage>472</epage><pages>463-472</pages><issn>0282-0080</issn><eissn>1573-4986</eissn><abstract>The introduction of type b
Haemophilus influenzae
conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>21850577</pmid><doi>10.1007/s10719-011-9344-3</doi><tpages>10</tpages></addata></record> |
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subjects | Algorithms Amines - chemistry Amines - immunology Bacterial Capsules - immunology Biochemistry Biomedical and Life Sciences Capsular polysaccharides Design optimization Developing Countries Diffusion Drug therapy glycoconjugates Haemophilus Infections - immunology Haemophilus Infections - prevention & control Haemophilus influenzae Haemophilus influenzae type b - immunology Haemophilus influenzae type b - pathogenicity Haemophilus Vaccines - chemical synthesis Haemophilus Vaccines - immunology Humans Hydrazines - chemistry Hydrazines - immunology Immunoconjugates - chemistry Immunogenicity Influenza Isoelectric points Life Sciences Lysine Lysine - chemistry Lysine - immunology Pathology Polysaccharides - chemistry Polysaccharides - immunology Polysaccharides, Bacterial - chemistry Polysaccharides, Bacterial - immunology Precipitation Research Design Salts Temperature effects Tetanus Tetanus Toxoid - chemistry Tetanus Toxoid - immunology Vaccination Vaccines Vaccines, Conjugate - chemistry Vaccines, Conjugate - immunology |
title | Experimental design to optimize an Haemophilus influenzae type b conjugate vaccine made with hydrazide-derivatized tetanus toxoid |
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